DESCRIPTION: Worldwide, 20 million people are infected with HTLV-1, a majority of which remain asymptomatic carriers (ACs), while a few develop ATL or HAM/TSP with no effective treatment or vaccine for either disease state. The exact mechanism(s) of disease pathophysiology remain unresolved with a big question of high proviral load in HAM/TSP patients despite vigorous cellular immune response (primarily directed towards viral transactivator protein Tax)? Our initial studies implicated programmed death (PD)-1 receptor and its ligand, PD-L1 as potential underlying factors for observed immune cells' dysfunctions leading to viral persistence and disease progression, primarily in HAM/TSP patients. PD-1:PD-L1/PD-L2 are the members of immunoglobulin superfamily (IgSF) co-signaling molecules and have been linked with CD8 T-cell exhaustion during chronic viral infections. Several members of this family including CTL-4:B7-1(CD80)/B7-2(CD86), LAG-3:HLA-DR, Tim- 3:Galectin-9, 2B4:CD48, and BTLA CD160:HVEM play critical role in regulating antigen-specific immune responses. Thus far, PD-1 and CTLA-4 pathways have been extensively studied; and blocking antibodies against these have shown clinical benefit in the setting of cancer. Further recent data suggest that blocking multiple inhibitory receptors simultaneously may improve T-cell based therapies, but further studies are required to clarify the role of each receptor-ligand pair. Moreover, the clinical applicability of PD-1 and CTLA-4 remains to be tested with respect to human chronic viral infections as well as neuroinflammatory diseases, such as HAM/TSP, NeuroAIDS, etc. Interestingly, HTLV-1 provides a good model for both and thus, we find it significant to investigate the role of key inhibitory receptors/ligands in HTLV-1 infection and tes their combined blockade as potential immunotherapeutic strategy to restore immune cell functions in HAM/TSP patients. While this approach should help in restoring functions of pre-existing antiviral immunity in patients, activating new CTLs to mimic polyclonal CD8 T-cell response found in ACs will be the key for a successful immunotherapeutic intervention of HTLV-associated diseases. Therefore, we propose to systematically identify T-cell epitopes presented by HTLV-1-infected cells that define protective immunity in silent carriers alongside blocking inhibitory pathways in order to fully restore T-cell functions in chronically infected patients. Th Specific Aims to achieve these goals are to 1) Investigate co-expression patterns of IgSF negative regulators and devise a blockade strategy to restore polyfunctionality and cytolytic potential of antigen-specific T-cells in HTLV-1 patient cohorts; 2) Perform extensive immunoproteomics analyses of MHC Class I:peptide complexes on the infected cells, and identify best candidate(s) for anti-HTLV-1 polyclonal T-cell response by comparative immunogenicity testing in carriers versus diseased individuals; and 3) Evaluate the combined strategy of restoring immune cell functions along with the expansion of cellular immune response using neo-epitopes in the context of HTLV-1-infected humanized mice. .